Stepwise pathogenic evolution of <em>Mycobacterium abscessus</em>

doi:10.1126/science.abb8699

GSTDTAP > 气候变化

DOI	10.1126/science.abb8699
	Stepwise pathogenic evolution of Mycobacterium abscessus
	Josephine M. Bryant; Karen P. Brown; Sophie Burbaud; Isobel Everall; Juan M. Belardinelli; Daniela Rodriguez-Rincon; Dorothy M. Grogono; Chelsea M. Peterson; Deepshikha Verma; Ieuan E. Evans; Christopher Ruis; Aaron Weimann; Divya Arora; Sony Malhotra; Bridget Bannerman; Charlotte Passemar; Kerra Templeton; Gordon MacGregor; Kasim Jiwa; Andrew J. Fisher; Tom L. Blundell; Diane J. Ordway; Mary Jackson; Julian Parkhill; R. Andres Floto
	2021-04-30
发表期刊	Science
出版年	2021
英文摘要	Mycobacteria are mostly environmental saprotrophs, but during human history, some have become our pathogens. In the past 50 years or so, intractable and virulent infections of Mycobacterium abscessus have emerged in people with cystic fibrosis. Bryant et al. investigated how these mycobacteria have evolved into human pathogens so quickly (see the Perspective by Brugha and Spencer). Chronic infections in the lung offer plenty of evolutionary scope for the emergence of virulent clones after horizontal gene transfer and hypermutation. Pathogens are acquired by environmental contamination, which leaves open a window for clinical control because the most virulent clones survive poorly outside the body. Therefore, immediate treatment and enhanced infection-control measures for M. abscessus cases could reduce opportunities for the evolution of direct person-to-person transmission. Science , this issue p. [eabb8699][1]; see also p. [465][2] ### INTRODUCTION Nearly all mycobacterial species are free-living environmental saprophytes. A few, such as Mycobacterium tuberculosis , have evolved to cause transmissible human infection and eventually to become obligate human pathogens. The recent emergence and global spread of virulent clones of the environmental nontuberculous mycobacterium M. abscessus has provided a unique opportunity to examine the pathogenic evolution of mycobacteria. ### RATIONALE M. abscessus , a multidrug-resistant species of nontuberculous mycobacteria, has recently emerged as a major threat to individuals with cystic fibrosis (CF) and other chronic lung conditions. Infection rates within the CF community are increasing globally, driven in part by indirect person-to-person transmission of M. abscessus. Currently more than 70% of infections in CF patients are caused by genetically clustered (and thus transmitted) isolates, of which the majority are from three dominant circulating clones (DCCs) that have emerged within the past 50 years and have spread globally. These clustered isolates are more virulent when tested in vitro and in vivo and result in worse clinical outcomes, which suggests that they are evolving from environmental saprophytes into obligate lung pathogens. We reasoned that functional genomic analysis of M. abscessus might identify important generalizable steps in this evolutionary trajectory and highlight potential interventions to mitigate this process for this and other emergent mycobacterial pathogens. ### RESULTS We initially sought to understand how the DCCs may have emerged. Using graphical pan-genome analysis, we found that horizontal gene transfer—particularly gene transfer of global transcriptional regulators—can provide an important mechanism for creating large phenotypic variance in environmental M. abscessus isolates, consequently enabling saltational evolution toward enhanced human infectivity. This process may be generalizable across mycobacterial species where gene gain or loss events have been associated with the pathogenic evolution of virulent clones in several species, including cluster 1a within M. avium , clone A within M. canettii , and the monophyletic M. tuberculosis complex from an M. canettii– like ancestor. We next examined whether ongoing adaptation of infecting M. abscessus clones could further promote pathogenicity. We reconstructed the evolutionary trajectories of individual M. abscessus subclones within chronically infected patients, identifying convergent allopatric evolution within and between individuals as a key driver for pathogenic adaptation. Specifically, recurrent mutations within a small set of genes from a single functional network are likely to drive enhanced macrophage survival and increased virulence in vivo. We observed reduced transmission fitness for many adaptive mutations. For two frequently mutated genes ( phoR and the GPL locus), knockouts showed impaired survival on fomites. These findings suggest that within-host evolution is constrained, while an environmental intermediary is required for transmission. ### CONCLUSION Our results point to a generalizable model for mycobacterial pathogenic evolution. Initially, horizontal gene acquisition by environmental clones (particularly of genes with global transcriptional effects) drives saltational evolution and increases virulence, giving rise to the ancestors of the dominant circulating clones of M. abscessus and driving the emergence of virulent clones in other mycobacterial species. Next, within-host adaptation during chronic infection drives increased intracellular survival within macrophages and inflammatory lung damage. However, pathogenic evolution is constrained while M. abscessus is transmitted through environmental intermediaries, because the most highly adapted strains lose transmission fitness through reduced fomite survival. Ultimately, we predict that opportunities for direct transmission of emergent mycobacteria (potentially through increases in population density and/or host susceptibility) will permit unconstrained, accelerated evolution into an obligate human pathogen (as occurred in M. tuberculosis several thousand years ago). Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict existing pathogens and prevent new, emergent ones. ![Figure][3] Steps involved in mycobacterial pathogenic evolution. (1) Horizontal gene acquisition by environmental clones drives saltational evolution and gives rise to the ancestors of the dominant circulating clones of M. abscessus (and virulent clones within other mycobacterial species). (2) Allopatric within-host adaptation during chronic infection drives increased intracellular survival within macrophages and inflammatory lung damage. (3) Evolution is constrained while M. abscessus is transmitted through environmental intermediaries because the most highly adapted strains lose transmission fitness through reduced fomite survival. (4) Opportunities for direct transmission of emergent mycobacteria (potentially through increases in population density and/or host susceptibility) permit unconstrained, accelerated evolution (as occurred in M. tuberculosis ). Although almost all mycobacterial species are saprophytic environmental organisms, a few, such as Mycobacterium tuberculosis , have evolved to cause transmissible human infection. By analyzing the recent emergence and spread of the environmental organism M. abscessus through the global cystic fibrosis population, we have defined key, generalizable steps involved in the pathogenic evolution of mycobacteria. We show that epigenetic modifiers, acquired through horizontal gene transfer, cause saltational increases in the pathogenic potential of specific environmental clones. Allopatric parallel evolution during chronic lung infection then promotes rapid increases in virulence through mutations in a discrete gene network; these mutations enhance growth within macrophages but impair fomite survival. As a consequence, we observe constrained pathogenic evolution while person-to-person transmission remains indirect, but postulate accelerated pathogenic adaptation once direct transmission is possible, as observed for M. tuberculosis . Our findings indicate how key interventions, such as early treatment and cross-infection control, might restrict the spread of existing mycobacterial pathogens and prevent new, emergent ones. [1]: /lookup/doi/10.1126/science.abb8699 [2]: /lookup/doi/10.1126/science.abi5695 [3]: pending:yes
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/325030
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Josephine M. Bryant,Karen P. Brown,Sophie Burbaud,et al. Stepwise pathogenic evolution of Mycobacterium abscessus[J]. Science,2021.
APA	Josephine M. Bryant.,Karen P. Brown.,Sophie Burbaud.,Isobel Everall.,Juan M. Belardinelli.,...&R. Andres Floto.(2021).Stepwise pathogenic evolution of Mycobacterium abscessus.Science.
MLA	Josephine M. Bryant,et al."Stepwise pathogenic evolution of Mycobacterium abscessus".Science (2021).